I. Cerebral protection and resuscitation

Cerebral protection. Cerebral protection is the preemptive use of therapeutic interventions to improve neurologic outcome in patients who will be at risk for cerebral ischemia. The primary objective is prevention of the deleterious effects of ischemia.
Resuscitation. Resuscitation refers to therapeutic interventions initiated after an ischemic event. The goal is treatment of ischemia and attenuation of neuronal injury.
 

II. The ischemic brain

Cerebral ischemia. Cerebral ischemia is defined as perfusion insufficient to provide the supply of oxygen and nutrients needed for maintenance of neuronal metabolic integrity (40% to 45% of total cerebral metabolic rate for oxygen consumption [CMRo₂]) and function (55% to 60% of CMRo₂). It is assumed that a hierarchy of ischemic damage exists in which neuronal function is abolished before cellular integrity is lost.
Cellular integrity. The brain utilizes glucose as its primary substrate for energy production. In the nonfasting state, glucose is metabolized via oxidative phosphorylation to adenosine triphosphate (ATP), which is needed for cellular activities such as homeostasis, protein synthesis, removal of carbon dioxide (CO₂), mitochondrial activity, and maintenance of ionic gradients and cell membrane stability.
Neuronal function. Normal neuronal functional activity consists of the generation and transmission of nerve impulses and is manifest by the presence of normal electroencephalographic (EEG) activity.
Ischemia. Ischemia may be global or focal, as well as complete or incomplete. Complete global ischemia occurs with cardiac arrest; incomplete global ischemia occurs with hypotension or shock. Focal ischemia involves the occlusion of a single vessel and is thus incomplete.
The ischemic cascade. The ischemic cascade occurs when inadequate cerebral perfusion leads rapidly to a cascade of pathophysiologic changes involving a multitude of chemical mediators of neuronal damage.
Decreased availability of oxygen and glucose results in immediate depletion of ATP, which is required for all active cellular processes. This depletion occurs within 2 to 4 minutes of complete ischemia. Phosphocreatine (PCr) is a source of high energy phosphate that allows the resynthesis of ATP from adenosine diphosphate (ADP). Brain PCr levels are normally three times those of ATP. A decrease in PCr is one of the earliest harbingers of ischemia.
Lactate levels increase because of anaerobic metabolism of glucose. Lactic acidosis aggravates ischemic damage. Lactic acid reduces ferric to ferrous iron, which in turn promotes free radical formation followed by lipid peroxidation of cell membranes. With incomplete ischemia, the persistence of residual perfusion facilitates increased lactate production in the presence of ongoing anaerobic metabolism and is thought to be the mechanism for increased damage with this type of ischemia. In contrast, complete ischemia results in complete cessation of metabolism.
Increased plasma glucose is an independent risk factor for aggravation of ischemia. The primary mechanism appears to be increased production of lactate with intracellular acidosis which contributes to neuronal necrosis. Hyperglycemia also prevents the increase in brain adenosine that occurs with ischemia. Adenosine, a purine nucleotide, inhibits excitatory amino acid (EAA) release and promotes cerebrovasodilatation, thus theoretically attenuating ischemic damage. In addition, there is some evidence that insulin has neuroprotective effects independent of its glucose-lowering properties. Hypoglycemia can also exacerbate ischemic brain injury. The persistence of hypoglycemia results in seizure activity and neuronal injury, particularly to the hippocampus.
Cerebral ischemia increases release of the EAA neurotransmitters glutamate and aspartate.
Three receptors for the excitatory neurotransmitters are currently identified.
(1) N-methyl-D-aspartate (NMDA) receptors are located in layers three, five, and six of the cerebral cortex, thalamus, striatum, and Purkinje fibers, the granule cell layers of the cerebellum, and the CA1 region of the hippocampus, which is particularly susceptible to ischemia. NMDA receptors mediate the influx of sodium (Na) and calcium (Ca) through membrane channels. Magnesium and the experimental drug dizocilipine maleate (MK-801) block the NMDA receptor site in a noncompetitive fashion.
(2) Quisqualate (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA]) receptors occur in the deep cortical layers, thalamus, striatum, molecular layer of the cerebellum, and pyramidal cell layer and striatum lucidum of the hippocampus. AMPA receptors mediate the influx of Na.
(3) Kainate receptors, located in the striatum lucidum of the hippocampus, also mediate the influx of Na.
Glutamate stimulates all three receptors, but aspartate affects only the NMDA receptor. The presence of glycine is necessary for activation of NMDA receptors by glutamate.
Glutamate causes neuronal cell death by two mechanisms: immediate and delayed. In immediate neurotoxicity, glutamate activates the NMDA receptor, leading to Na, chloride (Cl), and water (H2O) influx, which results in cellular edema, membrane lysis, and cell death. In delayed neurotoxicity (24 to 72 hours), the activated NMDA receptor promotes a cycle of ischemia initiated by the influx of Ca. This leads to activation of phospholipases, proteases, and eventually free fatty acids (FFAs), formation of arachidonic acid and free radicals, lipid peroxidation, and, ultimately, cell death.
Increased Ca influx is an early, pivotal event in the ischemic cascade and is caused by several mechanisms.
Depletion of ATP results in failure of the energy-requiring sodium/potassium (Na/K) ATPase-dependent ion pumps. Na and Cl influx and K efflux ensue. Influx of H₂O and edema occur secondarily. The resulting membrane depolarization leads to opening of voltage-sensitive Ca channels and Ca influx.
Decreased ATP leads to Ca release from endoplasmic reticulum.
EAA levels increase during ischemia, leading to stimulation of glutamate receptors and the opening of NMDA-mediated Ca channels.
Ca extrusion from the cell is an active process that stops when ATP stores are exhausted.
Numerous ischemic effects of Ca form a common pathway leading to neuronal cell destruction. Increased intracellular Ca activates phospholipase A1, A2, and C, which leads to the hydrolysis of membrane phospholipids and the release of FFAs.
Loss of membrane phospholipids also results in mitochondrial and cell membrane destruction.
Arachidonic acid. The major FFA, arachidonic acid, is metabolized to prostaglandins, leukotrienes, and free radicals. Both prostaglandins (via the cyclooxygenase pathway) and leukotrienes (via lipoxygenase) cause cerebral edema. Thromboxane A2, a prostaglandin derived from arachidonic acid with potent vasoconstrictor and platelet aggregation properties, potentiates ischemia and has been implicated in reperfusion injury.
Free radical formation. Superoxide, peroxide, and hydroxyl radicals cause lipid peroxidation within neuronal cell membranes. This alters membrane function and releases toxic by-products (aldehydes, hydrocarbon gases). These by-products cause edema, blood-brain barrier disruption, and inflammation. The superoxide radical itself can create an inflammatory response with vascular plugging.
 

Clinical ischemia

Of all body organs, the brain is the most vulnerable to ischemia. Loss of consciousness occurs within 15 seconds of cardiac arrest. Brain PCr becomes negligible within 1 minute. Glucose and ATP stores are exhausted within 4 to 5 minutes. Critical levels for cerebral blood flow (CBF), cerebral perfusion pressure (CPP, the difference between the mean arterial pressure [MAP] and the intracranial pressure [ICP]), and the partial pressure of arterial oxygen (Pao₂) have been determined below which cerebral ischemia occurs (Figure -1) with characteristic EEG changes.
Critical CBF is 18 to 20 mL/100 g of brain/minute. The penumbra is a hypoperfused region that may remain viable depending on timely reperfusion. The EEG becomes isoelectric at a CBF of 15 mL/100 g/minute. Metabolic failure occurs at a CBF of 10 mL/100 g/minute.
Critical CPP is 50 mm Hg in the normal individual.
Critical Pao₂ is 30 to 35 mm Hg in healthy awake patients.
Reperfusion injury refers to damage that occurs after the restoration of cerebral perfusion. An initial phase of hyperperfusion occurs, followed by a gradual decline in CBF referred to as the no-reflow phenomenon. Hypoperfusion results from thromboxane-induced vasoconstriction and platelet aggregation, impaired red cell deformability, tissue edema, and the persistence of abnormal Ca levels. In addition, intracellular acidosis, continued EAA, neurotransmitter and catecholamine release, and free radical formation contribute to delayed neuronal damage. This no-reflow phenomenon can last for up to 24 hours.

III. Clinical cerebral protection

Rationale for treatment. The goal is to maximize the available oxygen by increasing oxygen supply (delivery) and decreasing oxygen demand. Preservation of CBF and the avoidance of hypoxia and hypoxemia are critical.
Candidates for cerebral protection. Candidates for cerebral protection include patients who have the following characteristics:
Patients who have space-occupying lesions such as tumor, abscess, hematoma, hydrocephalus, and chronic cystic fluid collections with or without increased ICP who are scheduled for neurosurgical procedures.
Patients who are scheduled for intracranial vascular procedures, such as cerebral aneurysm coiling/clipping and excision of arteriovenous malformation (AVM) and cavernous angioma, and extracranial vascular procedures including carotid endarterectomy (CEA) and superficial temporal artery to middle cerebral artery (STA-MCA) bypass, which involve temporary vessel occlusion and the possibility of focal ischemia.
Patients who are scheduled for the clipping or coiling of giant or complex basilar artery aneurysms, which may be facilitated by deep hypothermic circulatory arrest (DHCA).
Cardiac bypass patients who typically are at risk from either global ischemia from low-flow states or focal ischemia from multiple small emboli.
Patients who have had a cardiac arrest with circulation reestablished within 2 hours.
 

IV. Clinical therapies

Nonpharmacologic treatment

Hypothermia decreases both metabolic and functional activities of the brain. Although hypothermia reduces CMRo₂ by roughly 7% for each degree Celsius, the mechanism is not uniformly linear. The temperature coefficient (Q₁₀), used to describe the relationship between temperature and CMRo₂, is the ratio of two CMRo₂ values separated by 10°C. For most biological reactions, the Q₁₀ is approximately 2 (a 50% decrease in CMRo₂ for every 10°C decrease in temperature). Thus, if the normothermic brain (37°C) can tolerate 5 minutes of complete ischemia, at 27°C the brain should tolerate 10 minutes of ischemia. The actual Q₁₀ is 2.2 to 2.4 between 37°C and 27°C, resulting in a reduction of >50% in CMRo₂ at 27°C. Between 27°C and 17°C, the Q₁₀ is approximately 5. This correlates with the gradual loss of neuronal function, as demonstrated by an isoelectric EEG (which occurs between 18°C and 21°C) and the ability of the brain to tolerate more prolonged ischemia than would be predicted based on a linear model. Below 17°C, the Q₁₀ is 2.2 to 2.4 again.
However, small decreases in temperature have also resulted in significant reductions in the damage from cerebral ischemia. Possible mechanisms of auxiliary hypothermic protection include decreased Ca influx, decreased EAA release, blood-brain barrier preservation, and prevention of lipid peroxidation. Although mild hypothermia (brain temperature of 32°C to 35°C) can be neuroprotective in the animal model, clinical evidence indicates that it is not beneficial during aneurysm surgery.
Correlation between esophageal and brain temperatures should not be assumed. Either tympanic membrane or nasopharyngeal temperature should therefore be measured as a more accurate estimate of brain temperature. Avoidance of hyperthermia is paramount because above-normal temperatures markedly increase CMRo₂ and exacerbate ischemic damage.
Deep hypothermic circulatory arrest to core temperatures of 13°C to 21°C might be indicated for clipping giant or complex basilar artery aneurysms. Peripheral arterial and large-bore intravenous catheters are inserted before induction of anesthesia. After induction, either a central venous or a pulmonary artery catheter, a second arterial catheter for phlebotomy, and a lumbar subarachnoid drain are inserted. Electrophysiologic monitoring of EEG, somatosensory evoked potentials (SSEPs), and brain stem auditory evoked potentials (BAEPs) is begun. The SSEPs persist to 15°C to 18°C and a CBF of 10 to 15 mL/100 g/minute, which is beyond hypothermic EEG isoelectricity (18°C to 20°C).
Cooling at a rate of 0.2°C/minute is performed by using a cooling blanket, infusing cold saline, and decreasing ambient temperature. Barbiturate-induced burst suppression is initiated and maintained intraoperatively. Hemodilution to a hematocrit of 28% to 30% is accomplished by phlebotomy; this blood is reserved in an anticoagulant solution to be reinfused after termination of bypass for replacement of essential clotting factors.
The aneurysm is dissected with meticulous attention to hemostasis before beginning femoral artery-femoral vein bypass. Heparin, 300 to 400 IU/kg, is administered, and the activated clotting time (ACT) is kept between 450 and 480 seconds. Cardiopulmonary bypass is begun when the patient's temperature is 34°C and continued until the desired core temperature is reached. Spontaneous atrial fibrillation may occur below 30°C, and continuous ventricular fibrillation frequently occurs below 28°C. To prevent myocardial ischemic injury, persistent ventricular fibrillation should be terminated by the administration of potassium chloride (KCl), 20 to 60 mEq. Cardioversion with 100 to 250 J may be used to induce asystole in patients resistant to KCl or in anephric patients in whom KCl is contraindicated. MAP should be maintained between 40 to 80 mm Hg during bypass.
Circulatory arrest occurs between 22°C and 18°C. The bypass pump is stopped. The duration of circulatory arrest is limited to aneurysm clip application time. Bypass is resumed and rewarming proceeds at 0.2 to 0.5°C/minute. Spontaneous ventricular fibrillation occurs with rewarming. Cardioversion (200 to 400 J) is required to restore sinus rhythm. Extracorporeal bypass is terminated when the patient's temperature reaches 34°C and normal sinus rhythm and cardiac output are present. Inotropic support may be required. The previously removed whole blood is reinfused to promote normal coagulation. Heparin is reversed with protamine to achieve an ACT of 100 to 150 seconds. Complications of this technique include coagulopathy, postoperative hemorrhage, metabolic acidosis, hyperglycemia, myocardial depression, and dysrhythmias.
Avoidance of hyperglycemia. The current recommendation is to keep the serum glucose below 150 mg/dL. Serum glucose is monitored frequently, and hypoglycemia (serum glucose below 60 mg/dL) is scrupulously avoided.
Avoidance of hypotension, hypoxia, and hypercapnia. The surgeon may request induced hypertension to improve CPP during temporary proximal occlusion of the parent vessel before definitive aneurysmal clip-ligation. Induced hypotension can be detrimental in patients at risk for vasospasm.
Hemodilution to a hematocrit of 32% to 34% increases CBF by decreasing viscosity, thereby improving oxygen delivery.
Normalization of increased ICP is achieved through moderate hyperventilation (partial pressure of arterial carbon dioxide [Paco₂] of 25 to 30 mm Hg), head elevation to 30° in the neutral position, mannitol and/or furosemide diuresis, cerebrospinal fluid (CSF) drainage via ventriculostomy, limited fluid restriction, and barbiturate coma in patients unresponsive to these techniques.
Correction of acidosis and electrolyte imbalance including Na and K abnormalities should be prompt.
 

Pharmacologic treatment

Barbiturates and erythropoietin remain the only drugs shown to be effective for pharmacologic cerebral protection against ischemic damage in humans.
Thiopental, a potent cerebrovasoconstrictor, decreases CMRo₂, CBF, cerebral blood volume (CBV), and ICP. CO₂ reactivity is preserved.
(1) The primary mechanism of protection involves a reduction in CMRo₂ of up to 55% to 60% at which point the EEG becomes isoelectric. Further reduction in CMRo₂ confers no additional protection. Thiopental's beneficial effects are thus limited to preservation of neuronal function.
(2) Thiopental may cause an inverse steal phenomenon whereby vasoconstriction in normal tissue improves perfusion of ischemic areas that are unable to vasoconstrict.
(3) Thiopental is an effective anticonvulsant.
(4) Other possible mechanisms include gamma-aminobutyric acid (GABA) agonism, free radical scavenging, membrane stabilization, NMDA antagonism, Ca channel blockade, and maintenance of protein synthesis.
(5) Thiopental does not improve outcome in global or complete ischemia after cardiac arrest.
(6) The thiopental dose in focal ischemia is 3 to 5 mg/kg every 5 to 10 minutes titrated to EEG burst suppression up to a total of 15 to 20 mg/kg. Maintenance of cardiovascular stability could determine the rate of administration.
Pentobarbital's cerebral effects are similar to those of thiopental. Pentobarbital is longer acting (t1/2 = 30 hours). The current clinical indication for pentobarbital is limited to barbiturate coma in patients who have increased ICP resistant to standard therapy. A loading dose of 3 to 10 mg/kg over 0.5 to 3 hours is given, followed by a maintenance infusion of 0.5 to 3 mg/kg/hour titrated to EEG burst suppression. The currently accepted therapeutic plasma concentration of pentobarbital is 2.5 to 4 mg/dL.
Methohexital, a short-acting barbiturate, can precipitate seizures in individuals who have epilepsy. Methohexital is useful for the induction of anesthesia for brief procedures in which seizure activity is desired (e.g., electroconvulsive therapy [ECT] and epilepsy surgery).
 

Other intravenous anesthetics. Anesthetic drugs that maintain ATP levels by decreasing cerebral metabolism while simultaneously preserving CBF and cardiovascular stability have theoretical potential for cerebral protection.
Etomidate is a short-acting imidazole compound which, like barbiturates, causes cerebral vasoconstriction. Electroencephalographic burst suppression occurs with higher doses. Most studies have not shown beneficial effects after cerebral ischemia. The administration of induction doses of etomidate has been associated with cerebral desaturation.
(1) Etomidate reduces CMRo₂ (by as much as 50%), CBF, and ICP while maintaining cardiovascular stability and CPP. CO₂ reactivity is preserved.
(2) Etomidate can cause adrenocortical suppression for up to 24 hours after a single induction dose (inhibition of 11 beta-hydroxylase). This may be of clinical concern when etomidate is used as an infusion, especially in patients who are not concomitantly receiving steroids.
(3) Myoclonic activity has been reported with etomidate, and seizures may occur.
(4) Side effects of etomidate include nausea, vomiting, and pain on injection.
Propofol (2, 6-diisopropylphenol), a short-acting induction drug also used to maintain anesthesia, has a cerebrovascular profile similar to that of barbiturates. Beneficial effects of propofol after brain ischemia have not been demonstrated.
(1) Propofol decreases CMRo₂, ICP, and CBF (via cerebrovasoconstriction). Hemodynamic depression decreases CPP more than with barbiturates.
(2) Burst suppression on EEG occurs with larger doses of propofol.
(3) Propofol may decrease postoperative nausea and vomiting.
Benzodiazepines, sedative-hypnotic drugs most commonly used as anesthetic adjuncts, stimulate the inhibitory neurotransmitter GABA and decrease CMRo₂ and CBF while preserving CO₂ reactivity. ICP may be decreased slightly. Benzodiazepines are potent anticonvulsants. They also produce amnesia and anxiolysis.
(1) Diazepam is used as an oral premedicant at a dose of 0.1 to 0.25 mg/kg. Its prolonged t1/2 of 21 to 37 hours limits its use in neurosurgical patients in whom prompt emergence and postoperative neurologic assessment are critical. Diazepam remains an effective treatment for status epilepticus.
(2) Midazolam has a t1/2 of 1 to 4 hours. The intravenous dose of midazolam for premedication is 0.5 to 2.5 mg up to 0.1 mg/kg. Excessive sedation and the possibility of hypoventilation-induced hypercapnia should be avoided in patients at risk for increased ICP. Midazolam in larger doses may have beneficial effects after brain ischemia.
(3) Lorazepam is also an effective premedicant in doses of either 0.5 to 4 mg by mouth or 2 to 4 mg intravenously (i.v.) or intramuscularly (i.m.). Like diazepam, its use is limited in neurosurgery by a t1/2 of 10 to 20 hours.
Opioids produce sedation and analgesia and cause a reduction in neurotransmitter release while preserving autoregulation, CO₂ reactivity, and cardiovascular stability. CBF, CMRo₂, and ICP are unchanged or slightly decreased. Delta waves are seen on EEG; burst suppression does not occur.
(1) Morphine is a potent analgesic with relatively poor central nervous system (CNS) penetration. Commonly used for postoperative analgesia in neurosurgical patients, morphine can cause hypotension secondary to histamine release.
(2) Meperidine may increase the heart rate because of its atropine-like structure and effect. Normeperidine is a metabolite of meperidine that can cause CNS excitation and seizures.
(3) Fentanyl is 100 times more potent than morphine. Fentanyl does not cause histamine release, is shorter acting than morphine, and decreases ICP and CBV slightly while maintaining CPP.
(4) Sufentanil is more potent than fentanyl and may increase ICP (via vasodilatation) in patients who have severe head trauma. The use of another opioid should be considered in such instances.
(5) Remifentanil is a very short-acting (t1/2 = 3 to 10 minutes) esterase-metabolized opioid that compared favorably to fentanyl in reduction of ICP and CBV and maintenance of CPP in a recent clinical trial.
Ca channel-blocking drugs should theoretically provide cerebral protection by vasodilatation and diminution of the consequences of Ca influx.
(1) Nimodipine decreases vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Nimodipine may increase CBF to underperfused areas by redistribution through an inverse steal effect. The dose of nimodipine, presently available only in oral form, is 60 mg every 4 hours for 21 days after SAH. Hypotension may occur with the administration of nimodipine.
(2) Nicardipine, available for intravenous administration, has decreased ischemic damage in animal studies, but clinical trials have not shown improved neurologic outcome after ischemia.
Ketamine, a phencyclidine derivative, produces dissociative anesthesia.
(1) Ketamine markedly increases ICP and CBF (60%) via cerebrovasodilatation. The CMRo₂ is unchanged or slightly increased. Autoregulation is abolished.
(2) Seizures can occur.
(3) Although it is a noncompetitive NMDA antagonist, ketamine is not recommended for patients who have intracranial pathology.
Local anesthetics are commonly used as adjuvants in neuroanesthesia.
(1) Lidocaine's clinical effects are determined by the dose. When administered after EEG isoelectricity induced by pentobarbital, lidocaine may decrease CMRo₂ by an additional 15% to 20%. At clinically recommended doses (1.5 mg/kg), lidocaine may reduce ischemic damage. Lidocaine also blunts the hemodynamic response to intubation by increasing anesthetic depth. At lower doses, lidocaine possesses anticonvulsant activity and can be used as ancillary therapy for status epilepticus. At toxic doses, lidocaine causes seizures.

Potent inhaled anesthetics

All potent inhaled anesthetics are cerebrovasodilatators and thereby increase CBF and ICP to different degrees. This effect can be attenuated by prior hyperventilation. The volatile anesthetics also decrease CMRo₂ while uncoupling CBF and CMRo₂. Autoregulation is impaired but CO₂ reactivity is preserved.
Isoflurane causes the greatest decrease in CMRo₂ (40% to 50%) and is the least potent vasodilator. The EEG becomes isoelectric EEG at 2 minimum alveolar concentration (MAC) or 2.4%. Isoflurane has no effect on the production of CSF but does increase CSF resorption. The critical CBF for isoflurane, the lowest of all the volatile agents, is 10 mL/100 g/minute. Thus, the use of isoflurane in patients undergoing CEA may have advantages. Isoflurane may also offer protection after brain ischemia. Studies of isoflurane in animal models of ischemia and hypoxemia have shown some limited protection from isoflurane. Preconditioning with isoflurane seems to confer tolerance to ischemia and some neuroprotection. In vitro studies have also shown improved recovery after ischemia and a reduction in cell death through the postischemic activation of ATP-regulated K channels and protein kinases.
The cerebral effects of sevoflurane are similar to those of isoflurane; both cause a slight increase in CBF and ICP and a decrease in CMRo₂. Nephrotoxic inorganic fluoride may accumulate when patients receive sevoflurane for prolonged periods of time. Induction and emergence are rapid. Sevoflurane may offer protection after brain ischemia through preconditioning. Preconditioning with sevoflurane and subsequent cerebral protection have been demonstrated during incomplete ischemia in vitro. Improved recovery in CA1 pyramidal cells in rats has occurred at clinical concentrations known to be useful in humans.
Desflurane is similar to isoflurane in its cerebrovascular profile, but ICP might increase despite normocapnia with desflurane compared to isoflurane. Induction and emergence with desflurane are rapid. Desflurane may also be protective after brain ischemia. Studies after hypoxia and after incomplete cerebral ischemia in rats have shown cerebral protective effects.
Nitrous oxide, a cerebrovasodilatator, increases CBF, CMRo₂, and ICP. The increase in CBF is attenuated by barbiturates, opioids, and hypocapnia. Nitrous oxide is 32 times more soluble in blood than nitrogen and is thus capable of diffusing into air-containing body cavities with extreme rapidity. Therefore, nitrous oxide is avoided in the presence of pneumocephalus and in any surgical procedure within 2 weeks of a craniotomy in which nitrous oxide was used. Nitrous oxide is also discontinued immediately if air embolism is suspected and may increase neurologic deficits after brain injury.

Anticonvulsant drugs are indicated in patients at risk for seizure activity including individuals who have epilepsy, head trauma, or craniotomy, and their administration is continued into the postoperative period. Seizure activity exacerbates the effects of ischemia through activation of anaerobic metabolic pathways. CBF, CMRo₂, and intracellular Ca increase during seizures, and EAA neurotransmitters, including glutamate, are released.
Once seizure activity occurs, the patient's airway is immediately secured and adequate ventilation is ensured to prevent hypoxemia and hypercapnia.
Avoidance of hypotension is essential.
Anticonvulsant therapy is administered promptly:
Thiopental, 25 to 100 mg i.v.
Diazepam, 2 to 20 mg i.v.
Midazolam, 1 to 5 mg i.v.
Fosphenytoin, 15 to 20 mg phenytoin equivalents (PE)/kg, or phenytoin, 15 mg/kg, may be administered to prevent further seizure activity once the acute episode has been terminated. Fosphenytoin, 75 mg, is equivalent to phenytoin, 50 mg, and has the advantage of increased speed of administration (up to 150 mg PE/minute). Phenytoin is limited to 50 mg/minute because it may induce hypotension. The loading dose of fosphenytoin can be given in 5 to 7 minutes, whereas the equivalent dose of phenytoin would require 15 to 20 minutes.
 

V. Cerebral preconditioning and neurogenesis
 

Models of cerebral ischemia in animals have shown that the induction of endogenous proteins of repair and genes that code for them can set the stage for cerebral preconditioning that may protect the brain during subsequent ischemia. Prodromal transient ischemic attacks (TIAs) may protect the brain during subsequent ischemic strokes. Recent evidence indicates that neurogenesis and diaschisis occur after injury. Diaschisis is a reduction in blood flow and metabolism in an area distant from the site of focal damage. It may represent a process of structural reorganization after injury. Apoptosis, or programmed cell death, may also be part of the process of structural reorganization after injury. Ischemia stimulates neurogenesis and new neurons migrate to the site of tissue injury and contribute to functional recovery. Activated neural stem cells contribute to stroke-induced neurogenesis and the migration of neuroblasts toward the infarct boundary in adult rats. Therapy for stroke in rats with a nitric oxide (NO) donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis subsequent to middle cerebral artery occlusion.
 

VI. Cerebral resuscitation
 

Patients who require resuscitation from cerebral ischemia include the following:
Intensive care unit (ICU) patients who have traumatic but nonoperative brain injury such as diffuse axonal injury (DAI) with increased ICP and cerebral edema who may be candidates for barbiturate coma.
Patients who have Reye's syndrome and cerebral edema with increased ICP.
Near-drowning victims who have anoxic encephalopathy, cerebral edema, and intracranial hypertension who are treated like Reye's syndrome patients.
Patients who have nonhemorrhagic stroke who may be candidates for fibrinolytic therapy with tissue plasminogen activator (TPA).
Anesthesiologists may encounter these patients when they are consulted about the management of cerebral edema and increased ICP or the induction and maintenance of barbiturate coma. These patients may also require sedation, analgesia, and neuromuscular blockade.
 

VII. Experimental modalities

NMDA receptor antagonists were developed to prevent neuronal damage from the excessive accumulation of the excitatory neurotransmitter glutamate. The NMDA receptor antagonists have not conferred consistently reproducible neuroprotection in experimental studies and may worsen injury. One of the difficulties has been the development of drugs that effectively penetrate the blood-brain barrier.
Dizocilpine maleate (MK-801) is a noncompetitive NMDA receptor antagonist whose beneficial effects in laboratory experiments may be partially attributable to drug-induced hypothermia. Dizocilpine is not approved for use in humans and does not appear to be promising.
Magnesium, a noncompetitive NMDA antagonist, binds within the ion channel, preventing ion flux, and may be helpful after brain injury.
Glycine binding site antagonism with HA-966 and 7-chlorokynurenic acid is still in the investigational stage but shows promise.
AMPA receptor antagonism with 2, 3-dihydroxy-6-nitro-7-sulfamoylbenzo (f)quinazoline (NBQX) has proved beneficial when given after the ischemic insult in experimental models.
Sodium channel-blocking drugs such as riluzole may reduce glutamate release during ischemia.
Lamotrigine, an anticonvulsant with Na channel-blocking activity, is known to reduce glutamate release and ischemic damage. Further studies are warranted.
Tirilazad, a lipid-soluble 21-aminosteroid, crosses the blood-brain barrier and acts as a lipid antioxidant, inhibiting free radical formation and lipid peroxidation. Studies indicate protection only when tirilazad is administered before an ischemic event.
Free radical scavengers. Superoxide dismutase (SOD), deferoxamine, vitamin E, mannitol, and glucocorticoids all possess free radical scavenging activity. The utility of SOD has been limited by its short t1/2 (8 minutes) and poor blood-brain barrier penetration. While glucocorticoids have membrane-stabilizing properties and decrease cerebral edema from brain tumors, they have not been shown to improve outcome in cerebral ischemia. The clinical usefulness of free radical scavengers is still under investigation.
Modification of arachidonic acid synthesis. Ischemia-induced excess of the vasoconstrictor thromboxane relative to the vasodilator prostacyclin (PGI2) has led to the development of thromboxane synthetase inhibitors and PGI2 synthetase stimulation to prevent the formation of excessive thromboxane.
Dexmedetomidine, an alpha₂ agonist, decreases central sympathetic activity by decreasing plasma norepinephrine release. Dexmedetomidine has been found to be neuroprotective in a model of focal ischemia, perhaps because excess catecholamine levels correlate with increased neuronal ischemic damage. Dexmedetomidine also decreases the MAC for halothane and isoflurane and decreases CBF without significantly altering CMRo₂.
NO is a free radical with complex neuronal activity. Nitric oxide synthase (NOS) catalyzes the formation of NO from the amino acid L-arginine, which itself decreases neuronal damage in experimentally induced focal ischemia. Three forms of NOS have been discovered:
Neuronal NOS (nNOS) enhances glutamate release and NMDA-mediated neurotoxicity. Selective nNOS inhibition has been shown to be neuroprotective.
Immunologic NOS (iNOS) is not detectable in healthy tissue. Induction of iNOS causes delayed neuronal cell death and can exacerbate glutamate excitotoxicity. Inhibition of iNOS by aminoguanidine reduces ischemic damage in experimental models.
Stimulation of endothelial NOS (eNOS) by an ischemia-induced increase in intracellular Ca improves CBF by dilatation of cerebral blood vessels and has been shown to reduce ischemic damage in a rodent model.

Erythropoietin (EPO) is a substance produced in the brain after hypoxic or ischemic insults. Primarily elaborated in the adult mammalian astrocytes in the ischemic penumbra, EPO stimulates neurogenesis, angiogenesis, and production of the proteins of repair, diminishes neuronal excitotoxicity, reduces inflammation, and inhibits neuronal apoptosis. It has been used in humans for cerebral preconditioning in patients after ischemic stroke. EPO may be more effective, however, as a prophylactic protectant when given preoperatively. Nonhematopoietic analogs of EPO, such as asialoEPO, have been developed and are showing equivalent potency as neuroprotectants in the laboratory. These analogs do not increase the hematocrit and thus do not exacerbate the ischemia injury through an increase in blood viscosity.
Other experimental modalities. Experimental results with preoperative hyperbaric oxygen, normobaric 100% oxygen exposure, electroconvulsive shock, and the potassium channel-opening drug, diazoxide, have shown that all of these modalities can be used to accomplish cerebral preconditioning.
Anesthesia duration and depth. Minimizing the duration of the time during which the patient is deeply anesthetized may provide cerebral protection by preventing neuronal apoptosis. A growing body of evidence indicates that cumulative deep anesthesia time is an independent predictor of increased postoperative mortality in adult patients.